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Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A
P L Yeyati1, R Shaknovich, S Boterashvili
1Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Abstract:
The PLZF gene was identified by its fusion with the RARalpha locus in a therapy resistant form of acute promyelocytic leukemia (APL) associated with the t(11;17)(q23;q21) translocation. Here we describe PLZF as a negative regulator of cell cycle progression ultimately leading to growth suppression. PLZF can bind and repress the cyclin A2 promoter while expression of cyclin A2 reverts the growth suppressed phenotype of myeloid cells expressing PLZF. In contrast RARalpha-PLZF, a fusion protein generated in t(11;17)(q23;q21)-APL activates cyclin A2 transcription and allows expression of cyclin A in anchorage-deprived NIH3T3 cells. Therefore, cyclin A2 is a candidate target gene for PLZF and inhibition of cyclin A expression may contribute to the growth suppressive properties of PLZF. Deregulation of cyclin A2 by RARalpha-PLZF may represent an oncogenic mechanism of this chimeric protein and contribute to the aggressive clinical phenotype of t(11;17)(q23;q21)-associated APL.
Insights
The PLZF gene suppresses cell growth by inhibiting cyclin A2. However, the RARalpha-PLZF fusion protein in acute promyelocytic leukemia activates cyclin A2, contributing to aggressive disease.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The promyelocytic leukemia zinc finger (PLZF) gene was identified through its fusion with the retinoic acid receptor alpha (RARalpha) in acute promyelocytic leukemia (APL) with t(11;17) translocation.
- This translocation results in a therapy-resistant form of APL, suggesting a role for the PLZF-RARalpha fusion protein in disease pathogenesis.
Purpose of the Study:
- To investigate the role of PLZF in cell cycle regulation and growth suppression.
- To identify target genes of PLZF and the RARalpha-PLZF fusion protein.
- To elucidate the mechanism by which RARalpha-PLZF contributes to aggressive APL.
Main Methods:
- Analysis of PLZF's effect on cell cycle progression.
- Investigation of PLZF binding and repression of the cyclin A2 promoter.
- Assessment of cyclin A2 expression in myeloid cells and NIH3T3 cells under different conditions.
- Comparison of PLZF and RARalpha-PLZF protein functions.
Main Results:
- PLZF acts as a negative regulator of cell cycle progression, leading to growth suppression.
- PLZF directly binds and represses the cyclin A2 promoter.
- Expression of cyclin A2 reverses the growth-suppressed phenotype induced by PLZF.
- The RARalpha-PLZF fusion protein activates cyclin A2 transcription, promoting cyclin A expression even in anchorage-deprived cells.
Conclusions:
- Cyclin A2 is a key target gene regulated by PLZF.
- Inhibition of cyclin A2 expression by PLZF contributes to its growth-suppressive effects.
- Deregulation of cyclin A2 by the RARalpha-PLZF fusion protein represents an oncogenic mechanism driving aggressive t(11;17)-associated APL.